Zinc Administration Research Articles

Profil Vulva dan Suhu Tubuh Kambing Peranakan Etawa pada Sinkronisasi Estrus Menggunakan Medroxy Progesterone Acetate dan Suplementasi Zinc (Zn)

Peranakan Etawa (PE) goat farming is one of the growing livestock sectors in Indonesia. Indonesia needs a sustainable breeding system that can guarantee the availability of goats. Estrus synchronization is a necessity that can help uniform the breeding time and manage the time of pregnancy and birth. Artificial estrus synchronization techniques that use a combination of Prosterone and Zinc minerals give good results of estrus synchronization in goats. The Aim of this research is to understand the combination efectiveness of estrus synchronization technique with progesterone acetate and Zinc supplementation. The design of this study used two treatment groups, each group consisting of three does PE goats. Estrus synchronization of experimental animals in treatment 1 and 2 was carried out using polyurethane sponge implant method which contained medroxi progesterone acetate 60 mg. Group 1 was given Sponge Progesterone for nine 9 days while giving Zinc (Zn) mineral supplement (Elemental Zn 20 mg, Kimia Farma) orally given 7 times. The frequency of Zinc administration every day begins during intra vaginal sponge insertion. Group 2 was treated same as group 1 with 14 days of implant time and 7 times of Zinc supplementation.The results showed that both treatments occurred estrus simultaneously with good estrus quality. Both treatments show the results of the estrus 8 score assessment with the estrus 3-9 range. The maximum estrus quality’s value of group 2 was higher (8.33 ± 0.57) compared to group 1 (8.0 ± 1.0). The estrus duration of group 2 occurs for 24 hours and group 1 for 7 hours. Estrus onset of Group 2 is earlier (58 hours) than group 1 (75 hours). Both treatment groups showed an increase in temperature at period of the occurrence of estrus. Body temperature during estrus time was 38.7 ± 0.20 0C to 39.60 ± 0.26 0C. The conclusion of this study is that in both treatments of estrus synchronization using sponge progesterone and zinc supplementation can cause estrus synchronization effectively . The duration of estrus in group 1 (9 days of implant) was Shorter than group 2 (14 days of implant). The onset of estrus time of group 1 (9 days of implant) was longer than Group 2 (14 days of implant). The body temperature of the experimental animals increases with the occurrence of estrus.

Selective Inhibition of HIF1α Expression by ZnSO4 Has Antitumoral Effects in Human Melanoma.

Zinc as an essential trace metal is a ubiquitous component of various molecules of the cell. Studies indicated that it may modulate functions of various cancer cell types, and can even inhibit metastasis formation in experimental models. In melanoma, zinc was shown to affect melanin production and to induce apoptosis. Using human melanoma cell lines, we have tested the effects of ZnSO4 on cell proliferation, survival, migration as well as in vivo on experimental liver colony formation. We have found that ZnSO4 has antiproliferative and proapoptotic effects in vitro. In SCID mice intraperitoneal administration of ZnSO4 specifically inhibited liver colony formation without affecting primary tumor growth. To reveal the molecular mechanisms of action of zinc in human melanoma, we have tested mRNA expression of zinc finger transcription factors and found a strong inhibitory effect on HIF1α, as compared to WT1 whereas HIF2α and MTF1 expression was unaffected. Immunohistochemical detection of HIF1α protein in liver metastases confirmed its decreased nuclear expression after in vivo ZnSO4 treatment. These data indicate that in human melanoma zinc administration may have an antimetastatic effect due to a selective downregulation of HIF1α.

Effects of Zinc on Non-alcoholic Fatty Liver Disease After Pancreatoduodenectomy

Background: The etiology, treatment and prevention of Nonalcoholic fatty liver disease (NAFLD) after pancreatoduodenectomy (PD) remain largely unknown. We aimed to elucidate the risk factors for NAFLD after PD and investigate the nutritional effects of zinc medication. Methods: We retrospectively examined 109 patients who underwent PD between 2013 and 2017. We diagnosed the postoperative NAFLD using CT attenuation at six months later. We identified the risk factors for postoperative NAFLD among perioperative factors and analyzed the nutritional effect of zinc medication at six months after surgery. Results: We diagnosed 27 patients with NAFLD after PD. A univariate analysis showed that pancreas cancer (p = 0.029), operative time (p = 0.008), blood loss (p = 0.034), postoperative diarrhea (p < 0.001) and zinc medication (p < 0.001) were associated with postoperative NAFLD. A multivariate analysis demonstrated that zinc medication was the most important factor for the prevention of NAFLD after PD. All patients who received zinc also took pancreatic enzyme simultaneously and showed a significantly lower rate of body weight loss than in patients without zinc at six months after PD (p = 0.041). These patients showed a significantly higher total cholesterol level (p = 0.006) and higher serum zinc level (p<0.001). Furthermore, significantly fewer cases of postoperative NAFLD were noted among the patients who received zinc than among those who did not receive it (5.7% vs 33.8%: p = 0.001). Conclusion: These results suggest that zinc administration might improve the postoperative nutritional status and prevent NAFLD after PD.

Long-term administration of excess zinc impairs learning and memory in aged mice.

Zinc (Zn) is an essential element, but excess amounts are known to cause neurotoxic effects. The risk of excessive Zn intake is increased by supplementing food intake with dietary supplements. Ageing affects many cellular processes that predispose individuals to neurodegeneration. Indeed, the prevalence of senile dementia such as Alzheimer's disease, Parkinson's disease, and vascular-type dementia increases with age. As such, we investigated the effects of long-term exposure to excess Zn on learning and memory in aged mice. ICR-JCL female mice (aged 26 weeks) were administered 0, 200, or 500 ppm Zn as zinc chloride in drinking water for 30 weeks. After 30-week administration, aged female animals were subjected to Y-maze, novel object recognition, and step-through passive avoidance tests. Chronic exposure to Zn did not inhibit learning and memory in the Y-maze test, but dose-dependently inhibited learning and memory in novel object recognition and step-through passive avoidance tests. These results indicate the potential for chronic Zn exposure to dose-dependently inhibit both long-term and novel object recognition memory. Results of microarray analysis revealed significant changes in gene expression of transthyretin and many olfactory receptors in the hippocampus of Zn-treated mice.

Meta-Analysis on the Effect of Zinc on Reducing Diarrhea Episode in Toddlers

Background: Diarrhea is a major cause of mortality and morbidity in toddlers in the world. A number of studies have shown that zinc supplements can reduce the severity and duration of diarrhea in toddlers. This study aimed to examine the effectiveness of zinc on reducing diarrhea episode in toddlers. Sub j ects an d Met h od: This was a meta-analysis conducted using PRISMA systematic guideline. Articles published between year 2000 and 2019 were selected from PubMed, Science Direct, and Springer Link databases. Six articles met the Randomized Controlled Trial (RCT) criteria. These studies were conducted in developing countries. A sample of 692 children divided into two groups of 348 zinc and 344 placebo. The data were analyzed by Review Manager (RevMan) 5.3 program. The results were assessed for Mean difference (MD) and the analysis was carried out for heterogeneity. Results: There was a high heterogeneity between experiments (I2 = 91%; p <0.001) so that Random Effects Model (REM) was used. Zinc administration reduced the duration of diarrhea 0.89 days faster than placebo, and it was statistically significant (MD= -0.89; 95% CI= -1.52 to -0.26; p= 0.006). Conclusion : Zinc supplementation is more effective than placebo in reducing the duration of diarrhea in children. Keywords : effectiveness, zinc, diarrhea, toddlers, meta analysis Cor r espondence : Purwika Widayati. Masters Program in Public Health, Universitas Sebelas Maret. Jl. Ir. Sutami 36A, Surakarta 57126, Central Java. Email: purwika15@gmail.com. Mobile: 081231153131. Indonesian Journal of Medicine (2019), 4(2): 183-191 https://doi.org/10.26911/theijmed.2019.04.02.12

Orexigenic action of oral zinc: metabolomic analysis in the rat hypothalamus.

We previously reported an orexigenic action of oral zinc administration in male Sprague-Dawley (SD) rats during an early stage of feeding with a zinc-deficient diet, without decreased zinc concentrations in tissues. The overall conclusion was that orally but not intraperitoneally administered zinc stimulates food intake in short-term zinc-deficient-diet fed rats. We here investigate the mechanism of the orexigenic action of zinc using GC-MS/MS-targeted metabolomic analysis in the rat hypothalamus. Four-week-old, male SD/Slc rats were used, and after 2days of feeding with a zinc-deficient diet, 3mg of ZnSO4 in 5mL saline solution were administered to each rat either orally or intraperitoneally. Three hours after administration, the rats were sacrificed and the hypothalamus were excised and analyzed. We found that the oral administration group showed increased concentrations of 3-aminopropanoic acid (β-alanine), hypotaurine, dopamine, and biotin. In light of metabolomic analysis of these results, we indicate directions for further research.

Zinc Supplementation Improves T Cell Reconstitution after Allogeneic HSCT By Stimulating Endogenous Pathways of Thymic Regeneration

Delayed T cell reconstitution after allogeneic hematopoietic stem cell transplant (allo-HSCT) is an important contributor to transplant-related morbidity and mortality due to infection and malignant relapse. Optimal T cell recovery requires a functional thymus, and strategies to enhance T cell reconstitution have the potential to improve overall outcome in allo-HSCT recipients, however, at the present time such strategies are limited. Hence one of the most significant clinical challenges is the need for rapid regeneration of thymopoiesis following induced immunodepletion and transplantation.Zinc is the second most abundant trace metal in the body, binding to more than 300 proteins involved in DNA synthesis and repair, gene transcription, cell proliferation as well as differentiation and apoptosis. Zinc deficiency (ZD) is a clinical condition causing immunosuppression and thymic atrophy with a consequent reduction in the number of circulating recent thymic emigrants (RTEs). Furthermore, mild ZD is one of the causes of the reduction in thymic function in the elderly and the role of zinc in tissue regeneration after damage has been clearly demonstrated in liver, skin, and intestinal diseases. In a pilot clinical trial, we demonstrated that patients receiving oral zinc supplementation after autologous HSCT showed increased thymic-dependent T cell reconstitution in the absence of adverse clinical events (Iovino 2018, Leuk Res). Although a clear clinical benefit was observed, the mechanisms underlying this process are poorly understood. Thus, we used a murine model to evaluate the effect of zinc supplementation in thymic reconstitution after acute damage.Using a model of thymic damage caused by sub-lethal total body irradiation (SL-TBI, 550 cGy), we found that mice that received zinc supplementation demonstrated increased thymic cellularity when compared to untreated age-matched mice (Fig. 1a). Importantly, this finding was also confirmed in a clinically-applicable model of MHC-matched allogeneic HSCT (Fig. 1b). We have previously demonstrated endothelial cells (EC), which are extremely resistant to damaged, are able to trigger thymic endogenous reconstitution after damage by producing regenerative factors such as BMP4, which targets thymic epithelial cells (TECs), a key population crucial for T cell development (Wertheimer 2018, Science Immunol). Interestingly, in our model of zinc administration, we found an increase in the number of regeneration-initiating ECs (Fig. 1c), and increased proliferation of TECs (Fig. 1d), which can occur in response to BMP4. Consistent with the hypothesis that zinc supplementation is activating the BMP4 pathway, when stimulated in vitro for 24 hours with supraphysiological doses of zinc sulfate, ex vivo propagated ECs (exECs) were directly induced to produce BMP4 (Fig. 1e), suggesting a likely mechanism by which zinc supplementation promotes thymic reconstitution.In conclusion, we demonstrate a mechanism by which zinc supplementation can improve thymic function and offers an innovative therapeutic strategy to improve T cell reconstitution in patients receiving allo-HSCT. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Zinc reduces antiseizure activity of neurosteroids by selective blockade of extrasynaptic GABA-A receptor-mediated tonic inhibition in the hippocampus

Zinc is an abundant trace metal in the hippocampus nerve terminals. Previous studies demonstrate the ability of zinc to selectively block neurosteroid-sensitive, extrasynaptic GABA-A receptors in the hippocampus (Carver et al, 2016). Here we report that zinc prevents the seizure protective effects of the synthetic neurosteroid ganaxolone (GX) in an experimental model of epilepsy. GABA-gated and tonic currents were recorded from dissociated dentate gyrus granule cells (DGGCs), CA1 pyramidal cells (CA1PCs), and hippocampal slices from adult mice. Antiseizure effects of GX and the reversal of these effects by zinc were evaluated in fully-kindled mice expressing generalized (stage 5) seizures. In electrophysiological studies, zinc blocked the GABA-evoked and GX-potentiated GABA-gated chloride currents in DGGCs and CA1PCs in a concentration-dependent fashion similar to the competitive GABA-A receptor antagonists bicuculline and gabazine. Zinc completely blocked GX potentiation of extrasynaptic tonic currents, but not synaptic phasic currents. In hippocampus kindling studies, systemic administration of GX produced a dose-dependent suppression of behavioral and electrographic seizures in fully-kindled mice with complete seizure protection at the 10 mg/kg dose. However, the antiseizure effects of GX were significantly prevented by intrahippocampal administration of zinc (ED50, 150 μM). The zinc antagonistic response was reversible as animals responded normally to GX administration 24 h post-zinc blockade. These results demonstrate that zinc reduces the antiseizure effects of GX by selectively blocking extrasynaptic δGABA-A receptors in the hippocampus. These pharmacodynamic interactions have clinical implications in neurosteroid therapy for brain conditions associated with zinc fluctuations.

Effect of administration of zinc and selenium on lipid peroxidation and endogenous antioxidant enzymes in trypanosoma brucei infected albino rats

Effect of administration of zinc and selenium on lipid peroxidation and endogenous antioxidant enzymes in trypanosoma brucei infected albino rats

Prevalence of Zinc Deficiency and Effect of Zinc Supplementation on Prevention of Acute Respiratory Infections: A Non Randomized Open Label Study

Background: Routine zinc supplementation is a potential intervention for the prevention of acute lower respiratory infections in developing countries. However discrepant findings from recent randomized trials remain unexplained. Methods: Single centre, single arm, prospective non-randomized, open label interventional study, of effect of zinc supplementation in zinc deficient children aged 6 months to 5 years. 465 healthy children aged 6 months to 5 years were enrolled in the study. The primary outcome was the prevalence of serum zinc deficiency. Children having zinc deficiency were recruited for the study of effect of oral administration of zinc 20 mg for 2 weeks. The secondary outcomes were incidence and duration of acute upper respiratory and acute lower respiratory infections per child-year and side effects after giving zinc therapy. Results: There was significant difference in mid arm circumference in between zinc deficient and non-zinc deficient groups (p < 0.001). Also the number of episodes of acute upper respiratory infections (AURI) and mean duration of AURI and acute lower respiratory infections (ALRI) was significantly different in the two groups (p < 0.001). There was no significant difference in ALRI episodes in two groups. After zinc supplementation in zinc deficient children, there was significant decrease in the number of episodes and mean duration of AURI (p < 0.001) and ALRI (p < 0.001) in six months after supplementation as compared to preceding six months before supplementation. Conclusion: This study sheds light on the efficacy of short course prophylactic zinc supplementation in reducing the burden of ARI among zinc deficient children. Future studies should assess the effectiveness of delivering prophylactic zinc supplementation at scale, comparing the feasibility and cost benefit of short course and continuous regimens. Clinical Trial Number: As it was a Non Randomized observational single arm study, study was not registered. Only RCT needs to be registered. Funding Statement: This study was funded by All India Institute of Medical Sciences (AIIMS), Manuscript Jodhpur, India, as a part of Intramural project conducted in the department of Pediatrics, AIIMS Jodhpur. Declaration of Interests: We declare no competing interests. Ethics Approval Statement: The study was approved by Institutional Ethics committee of All India Institute of Medical Sciences, Jodhpur, India. The study was conducted in accordance with ICH-GCP and other applicable regulatory guidelines.

English

In response to the high occurrence of diarrhea in Ethiopia, the Federal Ministry of Health employed an effective strategy that included administration of zinc together with oral rehydration salt to treat children suffered diarrhea since 2013. Nonetheless, information on zinc bundled with ORS uptake is limited and thus this study has examined zinc utilization among beneficiaries. A community based cross-sectional study was conducted among 422 households whose under-five- children (U5C) had diarrhea in Akaki sub city from February to March, 2016. Prior to selection of households, participants were identified through health facilities and were traced using their household number. Relevant socio-demographic and other important health information were collected from respective caretakers using a pre-tested structured questionnaire through interview. Data were then entered using Epi Info Version 3.5.4, exported and analyzed using SPSS version 20 software. Both bivariate and multivariate regression analyses were used to identify the factors related to zinc utilization and a p-value below 0.05 was considered as statistically significant. All recruited subjects participated in the study with 100% response rate. Of the 422 participants, 283 (67.1%) caretakers used zinc bundles with ORS when the under-five-child had diarrhea. The majority (82.2%) sought treatment from health centers though their major (80.90%) source for zinc was private pharmacies. Following zinc intake, diarrhea subsided within 1-3 days in most (76.3%) of them. About the same proportion of caretakers recommended the zinc for watery diarrhea and the vast majority (90.5%) were satisfied with zinc supplement. Caregivers' whose child diarrhea stopped were more likely (AOR=10.29; 95% CI=2.52-42.05) to use zinc while those whose child diarrhea stopped after six days (AOR=0.09; 95% CI=0.02-0.45) and had mucoid diarrhea (AOR=0.32; 95% CI=0.10-0.97) were less likely to give their children the zinc than their counterparts. The study thus revealed that slightly over two in three children were given diluted zinc and the major augmenting factors for the zinc bundled with ORS uptake were withholding to administer the full dose, stopping the drug when diarrhea improved and recommending zinc therapy. It is thus essential to consider the above determinants, avail the zinc in the government facilities, improve zinc bundled with ORS intake and ultimately reduce deaths emanating from diarrhea. Key words: Diarrhea, Zinc utilization, determinants, cross sectional community based study, Ethiopia

Potential role of zinc in the visceromegaly regression and recovery of hematological parameters during treatment of visceral leishmaniasis in children from an endemic area.

ABSTRACTLeishmaniasis is a disease complex with various clinical symptoms caused by different species of parasites of the genus Leishmania. The visceral form of the disease, characterized by severe symptoms is fatal, if not treated. The high toxicity of current antileishmanial drugs and the need for long-term treatment make the therapy complicated, especially in a large number of infected children. Hence, the search for new therapies must be intensified. Oral administration of the trace element zinc has been considered in alternative treatments against different clinical forms of leishmaniasis. This study revealed that the administration of zinc in children with visceral leishmaniasis, during treatment with amphotericin B or glucantime, accelerates the regression of the spleen enlargement without interfering with the recovery of hematological parameters.

Adjunctive Treatments for the Prevention of Chemotherapy- and Radiotherapy-Induced Mucositis.

Background: Chemoradiotherapy-associated mucositis can manifest as pain, inflammation, dysphagia, diarrhea, weight loss, rectal bleeding, and infection. Mucositis is a major dose-limiting side effect of chemotherapy, affecting nutritional intake and oral and intestinal function. Despite several interventions being available, there is a need for safe and effective preventative and treatment options for treatment-induced mucositis. The goals of this review are to discuss interventions based on foods and natural products and present the research to date. Methods: A narrative literature review identified 60 clinical studies examining various nutritional compounds and 20 examining probiotics. 9 studies on probiotics for the prevention of diarrhea were also assessed on methodological quality and limitations identified. Results: Several compounds have been posited as useful adjuvants for cancer treatment–related mucositis. Probiotics demonstrate efficacy for the prevention and treatment of chemoradiotherapy-induced gastrointestinal toxicity without significant side effects. Glutamine and activated charcoal were reported to reduce chemotherapy-induced diarrhea but not radiation-induced intestinal mucositis. Honey has been reported to decrease treatment interruptions, weight loss, and delays the onset of oral mucositis. Zinc, glutamine, and topical vitamin E were demonstrated efficacy for oral mucositis. Conclusion: There is plausible clinical evidence for the administration of several adjunctive treatments for the prevention and treatment of mucositis. Probiotics were reported to reduce the burden of intestinal mucositis and treatment-induced diarrhea. Activated charcoal and glutamine are beneficial for chemotherapy-induced diarrhea, whereas the administration of honey, zinc, and glutamine reduce the risk of developing oral mucositis during chemotherapy or radiotherapy.

Effect of Zinc on Spermatogenesis and Sperm Chromatin Condensation in Bleomycin, Etoposide, Cisplatin Treated Rats.

Objective The incidence rate of testicular cancer among young males is high. Co-administration of bleomycin, etoposide and cisplatin (BEP) has increased survival rate of patients with testicular cancer. Although BEP is one of the most effective treatment for testicular cancer, but it severely affects the reproductive system that ultimately leads to infertility. In addition to its antioxidant activity, zinc has an important role in progression of spermiogenesis. This study aimed to evaluate the effect of zinc on sperm parameters, chromatin condensation and testicular structure after BEP treatment. Materials and Methods In this experimental study, 40 male rats were divided into 4 groups (control, BEP, BEP+ zinc and zinc) and examined for 2 spermatogenesis periods (i.e. 18 weeks). The rats in BEP and BEP+ zinc group were treated with BEP at appropriate doses (0.75, 7.5, and 1.5 mg/kg) for three cycles of three weeks. Zinc at a dose of 10 mg/kg/day was administered to BEP+ zinc and zinc groups. After 18 weeks, we assessed sperm parameters, and excessive histone in sperm chromatin using aniline blue staining, as well as testicular structure and germ line cells using periodic acid-Schiff staining. Results After BEP treatment, significant decreases were observed in normal sperm morphology, motility, and concentration, as well as alterations in rat sperm chromatin condensation and testicular tissue (P<0.001). Furthermore, after zinc consumption for 9 weeks, we observed significant improvements of sperm parameters and chromatin condensation as well as a significant retrieval of spermatogonia, leydig cells and tubular architecture (P<0.05). ConclusionZinc administration after chemotherapy with BEP in testicular cancer might be potentially useful in declining the off target consequence associated with oxidative stress.

Clarification of the Mechanism Involved in Orexigenic Action by Oral Zinc Ingestion

We investigated the role of zinc in regulation of food intake using male SD rats during early-stage of zinc deficiency (the 3rd day of the feeding) without decreased zinc concentrations in tissues (hypothalamus and liver). As a result, we found that orally but not intraperitoneal administered zinc stimulates food intake in the short-term zinc-deficient rats. The mRNA expressions of hypothalamic peptides, such as orexin (OX) and neuropeptide Y (NPY), were increased after oral administration of zinc to increase food intake. Pretreatment with an antagonist for the NPY Y1 receptor or the orexin OX1 receptor blocked orexigenic activity by zinc administration. The stimulation of food intake by oral administration of zinc was also abolished by vagotomy. Taken together, our results indicate that zinc stimulates food intake in short-term zinc-deficient rats through the afferent vagus nerve followed by activating the hypothalamic peptide associated with food intake regulation. This study showed the first evidence that gastrointestinal zinc signal is indispensable for the food appetite induction in the experimentally anorexigenic rat. However, since it has not yet been clarified the mechanism involved in zinc sensing by the epithelial membrane of the gastrointestinal tract, further detailed investigations are necessary.

Improvement of symptoms in a rat model of depression through combined zinc and folic acid administration via up-regulation of the Trk B and NMDA

The aim of this study was to observe the influence of combined zinc and folic acid administration on depression and to explore its mechanism of action. Male Sprague Dawley rats were randomly divided into five groups: control, model, paroxetine (P), zinc + folic acid (ZnY), and zinc + folic acid + paroxetine (ZnYP) groups. Rat models of depression were established by chronic mild unpredictable stress for three weeks. These rats were then treated with different interventions for four weeks and the sucrose preference test was then performed to observe changes in rats’ behavior. An HPLC-electrochemical method was used to detect the levels of 5-hydroxytryptamine (5-HT), dopamine (DA) and norepinephrine (NE) in the frontal cortex. qRT-PCR was employed to detect the mRNA levels of tyrosine kinase receptor B (Trk B) and N-methyl-D-aspartate acid (NMDA) in the frontal cortex; Western blotting was used to detect the protein levels of brain derived neurotrophic factor (BDNF) in the frontal cortex. The results showed that compared with the model group, sucrose consumption, 5-HT, NE and DA levels were significantly increased in the ZnY group (P < 0.05). Also the mRNA levels of Trk B and NMDA were significantly increased in the ZnY group compared with the model group (P < 0.001). No significant up-regulation of BDNF was observed in the ZnY group. We conclude that combined administration of zinc and folic acid can improve the symptoms of depression-model rats, and its mechanism is related to increased levels of 5-HT, DA and NE in the brain, and to the up-regulation of Trk B and NMDA.

Plasma Malondialdehid and Histopatology Healing Score Differences in Incised Old and Young Mice Zinc with Zinc Administration

Free radical plays role in wound healing. This study was conducted to determinedifferences in level of plasma malondialdehyde (MDA), and histopathological score of woundhealing by administering zinc in old and young mice. We used 24 old mice and 24 young miceincision wound model, randomized into two groups, with and without zinc administration. Wefound plasma MDA level was lower in old mice with zinc administration but not statisticallysignificant. The plasma MDA level was significantly higher by administering zinc in young mice(p=0.004). The plasma MDA level of young mice was higher than old mice in zincadministration group (p=0.010). Reepitelialization, inflammatory cells, fibroblasts andangiogenesis did not differ by administering zinc both in old mice and young mice.Reepitelialization, inflammatory cells and angiogenesis did not differ between old and youngmice in mice that were given zinc; while fibroblast of young mice is more than old mice(p=0.010). We concluded plasma MDA level is higher in young mice with zincadministration. Plasma MDA level in young mice is higher than old mice with zincadministration. Young mice with zinc administration have higher fibroblast than oldmice.Keywords: aging, free radical, histopathologic score, malondialdehid, wound healing, zinc

Prophylactic Zinc and Therapeutic Selenium Administration Increases the Antioxidant Enzyme Activity in the Rat Temporoparietal Cortex and Improves Memory after a Transient Hypoxia‐Ischemia

In the cerebral hypoxia-ischemia rat model, the prophylactic administration of zinc can cause either cytotoxicity or preconditioning effect, whereas the therapeutic administration of selenium decreases the ischemic damage. Herein, we aimed to explore whether supplementation of low doses of prophylactic zinc and therapeutic selenium could protect from a transient hypoxic-ischemic event. We administrated zinc (0.2 mg/kg of body weight; ip) daily for 14 days before a 10 min common carotid artery occlusion (CCAO). After CCAO, we administrated sodium selenite (6 μg/kg of body weight; ip) daily for 7 days. In the temporoparietal cerebral cortex, we determined nitrites by the Griess method and lipid peroxidation by the Gerard-Monnier assay. qPCR was used to measure mRNA of nitric oxide synthases, antioxidant enzymes, chemokines, and their receptors. We measured the enzymatic activity of SOD and GPx and protein levels of chemokines and their receptors by ELISA. We evaluated long-term memory using the Morris-Water maze test. Our results showed that prophylactic administration of zinc caused a preconditioning effect, decreasing nitrosative/oxidative stress and increasing GPx and SOD expression and activity, as well as eNOS expression. The therapeutic administration of selenium maintained this preconditioning effect up to the late phase of hypoxia-ischemia. Ccl2, Ccr2, Cxcl12, and Cxcr4 were upregulated, and long-term memory was improved. Pyknotic cells were decreased suggesting prevention of neuronal cell death. Our results show that the prophylactic zinc and therapeutic selenium administration induces effective neuroprotection in the early and late phases after CCAO.

Targeting the Prion-like Aggregation of Mutant p53 to Combat Cancer.

Prion-like behavior of several amyloidogenic proteins has been demonstrated in recent years. Despite having functional roles in some cases, irregular aggregation can have devastating consequences. The most commonly known amyloid diseases are Alzheimer's, Parkinson's, and Transmissible Spongiform Encephalopathies (TSEs). The pathophysiology of prion-like diseases involves the structural transformation of wild-type (wt) proteins to transmissible forms that can convert healthy proteins, generating aggregates. The mutant form of tumor suppressor protein, p53, has recently been shown to exhibit prion-like properties. Within the context of p53 aggregation and the search for ways to avert it, this review emphasizes discoveries, approaches, and research from our laboratory and others. Although its standard functions are strongly connected to tumor suppression, p53 mutants and aggregates are involved in cancer progression. p53 aggregates are heterogeneous assemblies composed of amorphous aggregates, oligomers, and amyloid-like fibrils. Evidence of these structures in tumor tissues, the in vitro capability for p53 mutants to coaggregate with wt protein, and the detection of cell-to-cell transmission indicate that cancer has the basic characteristics of prion and prion-like diseases. Various approaches aim to restore p53 functions in cancer. Methods include the use of small-molecule and peptide stabilizers of mutant p53, zinc administration, gene therapy, alkylating and DNA intercalators, and blockage of p53-MDM2 interaction. A primary challenge in developing small-molecule inhibitors of p53 aggregation is the large number of p53 mutations. Another issue is the inability to recover p53 function by dissociating mature fibrils. Consequently, efforts have emerged to target the intermediate species of the aggregation reaction. Φ-value analysis has been used to characterize the kinetics of the early phases of p53 aggregation. Our experiments using high hydrostatic pressure (HHP) and chemical denaturants have helped to clarify excited conformers of p53 that are prone to aggregation. Molecular dynamics (MD) and phasor analysis of single Trp fluorescence signals point toward the presence of preamyloidogenic conformations of p53, which are not observed for p63 or p73. Exploring the features of competent preamyloidogenic states of wt and different p53 mutants may provide a framework for designing personalized drugs for the restoration of p53 function. Protection of backbone hydrogen bonds (BHBs) has been shown to be an important factor for the stability of amyloidogenic proteins and was employed to identify and stabilize the structural defect resulting from the p53 Y220C mutation. Using MD simulations, we compared BHB protection factors between p53 family members to determine the donor-acceptor pairs in p53 that exhibit lower protection. The identification of structurally vulnerable sites in p53 should provide new insights into rational designs that can rapidly be screened using our experimental methodology. Through continued and combined efforts, the outlook is positive for the development of strategies for regulating p53 amyloid transformation.

Effect of Zinc and Melatonin on Oxidative Stress and Serum Inhibin-B Levels in a Rat Testicular Torsion–Detorsion Model

The present study was aimed to examine the effects of 3-week zinc and melatonin administration on testicular tissue injury and serum Inhibin-B levels caused by unilateral testicular torsion-detorsion in rats. The study was performed on 60 Wistar Albino-type adult male rats. The animals were allocated to 6 groups in equal numbers. 1. Control; 2. Sham; 3. Ischemia-reperfusion; 4. Zinc+ischemia-reperfusion; 5. Melatonin+ischemia-reperfusion; 6. Zinc+melatonin+ischemia-reperfusion. Zinc and melatonin were administered before ischemia-reperfusion at doses of 5 and 3mg/kg respectively, by intraperitoneal route for a period of 3weeks. Testicular torsion-detorsion procedures consisted of ischemia for 1h and then reperfusion for another hour of the left testis. Blood and testicular tissue samples were collected to analyze erythrocyte and tissue GSH and plasma and tissue MDA, Inhibin-B levels. The highest erythrocyte and testis GSH values were found in zinc, melatonin, and zinc+melatonin groups (p<0.001). Torsion-detorsion group has significantly lower erythrocyte GSH levels and higher plasma MDA values (p<0.001). Serum inhibin-B and spermatogenic activity levels in the torsion-detorsion group were also significantly lower than those in the other groups (p<0.001). However, zinc-, melatonin-, and melatonin+zinc-supplemented groups have higher inhibin-B and spermatogenetic activity (p<0.001). The results of the study show that zinc, melatonin, and melatonin+zinc administration partially restores the increased oxidative stress, as well as the reduced inhibin-B and spermatogenic activity levels in testes ischemia-reperfusion in rats. Suppressed inhibin-B levels in the testicular tissue may be a marker of oxidative stress.